Visceral pain causes suffering and dysfunction in malignant and inflammatory states. Less is known about the mechanisms and neural systems involved in visceral than in cutaneous pain. Although the spinothalamic tract signals both cutaneous and visceral pain, a neurosurgical midline lesion in the dorsal column can relieve pelvic cancer pain, sparing cutaneous sensation and pain. HYPOTHESIS 1 is that a pathway that signals the pain of visceral distention ascends in the dorsal column. SPECIFIC AIM 1 is to see if a lesion reduces the responses of VPL neurons to noxious colorectal distention. HYPOTHESIS 2 is that the visceral nociceptive pathway is a part of the postsynaptic dorsal column pathway. SPECIFIC AIM 2 is to determine the source, destination, and peptide content of the pathway. Anatomical and electrophysiological experiments are planned to record responses to colorectal distention of postsynaptic dorsal column neurons and dorsal column nucleus and to determine if visceral responses of gracile neurons are signaled by postsynaptic dorsal column neurons rather than by direct primary afferent projections. HYPOTHESIS 3 is that the pathway is also responsible for signaling visceral inflammatory pain. SPECIFIC AIM 3 is to inflame the colon and to determine if 1) the responses of neurons become enhanced following visceral inflammation; 2) the enhanced responses of VPL neurons are reduced or prevented by a lesion interrupting the pathway; 3) the same lesions prevent brainstem cell groups from staining for c-FOS. HYPOTHESIS 4 is that visceral inflammatory pain causes central sensitization. SPECIFIC AIM 4 is to investigate mechanisms of the sensitization resulting from visceral inflammation by determining 1) the amino acids released into the dorsal horn during colon inflammation; 2) if dorsal root reflexes develop during colon inflammation; 3) if the sensitization can be reduced by infusing antagonists of excitatory amino acid, GABA(A) or peptide receptors into the dorsal horn at L6-S1; and 4) the peptide gene regulation and expression before and after the pharmacological manipulations. The long-term goal is to develop new strategies for therapy of visceral pain.